The anterior pituitary secretes several hormones which play a major role in metabolic functions. Among the most important of these hormones are the following: (1) thyroid-stimulating hormone (TSH) which stimulates the thyroid gland; (2) adrenocorticotropic hormone (ACTH) which stimulates the adrenal cortex to secrete cortisol; (3) growth hormone (GH) which stimulates body growth under certain circumstances; (4) follicle-stimulating hormone (FSH) which stimulates the ovaries in females and the testes in males; (5) luteinizing hormone (LH) which also stimulates the ovaries in females and the testes in males; and (6) prolactin (PRL) which stimulates secretion of milk from the breast.
The hypothalamus regulates many of the functions of the anterior pituitary by secreting a corresponding hypothalamic releasing factor which stimulates the secretion of the anterior pituitary homones. The several known hypothalamic releasing hormones include thyrotropin-releasing hormone (TRH) which stimulates the release of TSH; corticotropin-releasing hormone (CRH) which stimulates the release of ATCH; growth hormone releasing hormone (GRH); luteinizing hormone-releasing hormone or gonadotropin-releasing hormone (LHRH or GnRH) which stimulates the release of both LH and FSH; and prolactin-releasing hormone (PRH).
In evaluating the anterior pituitary function to secrete hormones, current methods involve the administration of hypothalamic releasing hormones to a patient. Assessment of anterior pituitary hormone function has been greatly facilitated by the availability of synthetic analogues of hypothalamic releasing hormones. The use of TRH and GnRH is routinely employed as specific provocative tests for assessment of anterior pituitary hormonal function. Rebar, R. W., Practical Evaluation of Hormonal Status. In: Yen, S. S. C. and Jaffe, R. B. (eds.). Endocrinology: Physiology, Pathophysiology and Clinical Management. Philadelphia: W. B. Saunders Co., (1978) pp. 469-518.
Recently, synthetic ovine corticotropin-releasing hormone (CRH) has been employed for assessing ACTH release from the anterior pituitary. Chrousos et al., "The Corticotropin-Releasing Factor Stimulation Test: an Aid in the Evaluation of Patients with Cushing's Syndrome," N. Engl. J. Med., 310: 622-626 (1984); DeBold et al., "Effect of Synthetic Ovine Corticotropin-releasing Factor: Prolonged Duration of Action and Biphasic Response of Plasma Adrenocorticotropin and Cortisol", J. Clin. Endocrinol. Metab., 57: 294-298 (1983); and Orth et al., "Effect of Synthetic Ovine Corticotropin-releasing Factor: Dose Response of Plasma Adrenocorticotropin and Cortisol, J. Clin. Invest, 71: 587-595 (1983).
Simultaneous sequential admission of hypothalamic releasing hormones has also been employed for determination of pituitary hormone function. Besser, G. M. et al., "Interaction Between Thyrotrophin, Coricotrophin and Growth Hormone Secretion in Man," J. Endocrinol, 51: 699-706 (1971); Harsoulis, P. et al., "Combined Test for Assessment of Anterior Pituitary Function," Br. Med. J., 4: 326-329 (1973); Lufkin, E. G. et al., "Combined Testing of Anterior Pituitary Gland with Insulin, Thyrotropin-releasing Hormone, and Luteinizing Hormone-releasing Hormone," Am. J. Med., 75: 471-475 (1983); and Mortimer, C. H. et al., "Interaction Between Secretion of the Gonadotrophins, Prolactin, Growth Hormone, Thyrotrophin and Corticosteroids in Man: the Effects of LH/FSH-RH, TRH and Hypoglycaemia Alone and in Combination," Clin. Endocrinol. (Oxf) 2: 317-326 (1973).
A recent study describes a rapid sequential intravenous administration procedure utilizing four hypothalamic releasing hormones which measures pituitary ACTH, FSH, LH, TSH, and PRL secretory function. Sheldon, W. R. Jr. et al., "Rapid Sequential Intravenous Administration of Four Hypothalamic Releasing Hormones as a Combined Anterior Pituitary Function Test in Normal Subjects," J. Clin. Endocrinol. Metab., 60: 623-630 (1985).
These current tests assess the secretion response of the anterior pituitary to a hypothalamic releasing hormone stimulus. None of these provocative tests, however, evaluate hypothalamic function to secrete releasing hormone. Moreover, since each hypothalamic releasing hormone is relatively specific for stimulating anterior pituitary hormone release, a single hypothalamic releasing hormone administration cannot evaluate multiple hormone secretions from the anterior pituitary. Thus, the current tests require the intravenous administration of a combination of several hypothalamic releasing hormones or require the intravenous, sequential administration of a series of hypothalamic releasing hormones over a period of time.
The inventor has discovered that 14-hydroxydihydronormorphinone derivatives can be used to assess multiple anterior pituitary hormone release as a consequence of the derivatives' ability to stimulate the hypothalamus. One of these derivatives, naltrexone, an opiate antagonist, is currently utilized in conventional medical practice as a pharmacologic adjunct for the treatment of opioid dependence.
Previous studies have shown that naltrexone increases plasma LH levels in normal adults. Briski et al., "Endogenous Opiate involvement in Acute and Chronic Stress-Induced Changes in Plasma LH Concentrations in the Male Rat," Life Science, 34: 2485-93 (1984); Veldhuis et al., "Endogenous Opiates Modulate the Pulsatile Secretion of Biologically Active Luteinizing Hormone in Man," J. Clinical Invest., 72: 2031-40 (1983); Mendelson et al., "Heroin and Naltrexone Effects on Pituitary Gonadal Hormones in Man: Interaction of Steroid Feedback Effects Tolerance and Super Sensitivity," J. Pharmacol. Exp. Ther., 214: 503-506 (1980); and Cicero et al., Endogenous Opioids Participate in the Regulation of the Hypothalamus-Pituitary-Luteinizing Hormone Axis and Testosterone's Negative Feedback Control of Luteinizing Hormone," Endocrinology, 104: 1286-91 (1979).
The use of naltrexone to stimulate release of other anterior pituitary hormones has also been studied. Atkinson, R. L., "Endocrine and Metabolic Effects of Opiate Antagonists," J. Clinical Psychiatry, 45: 9, Part 2 at 20-24 (1984).
However, it was not known that the oral administration of naltrexone can be useful as a single provocative stimulus for the release of multiple anterior pituitary hormone functions, including LH, FSH, prolactin, and ACTH. The inventor has found that hypothalamic function can be assessed by measuring the anterior pituitary hormone release in response to the stimulus from the administration of a 14-hydroxydihydronormorphinone derivative to the patient. Moreover, the inventor has found that administration of the 14-hydroxydihydronormorphinone derivatives during the early follicular phase of the female menstrual cycle is most effective for assessing hypothalamic function which regulates the release of anterior pituitary hormones.